For any given cancer, there exists a wide spectrum of clinical behavior. Understanding the factors that influence tumors approach to risk assessment and the design of therapy. Inherited variation of certain genes and their interaction with the environment are thought to govern, to a large extent, tumor heterogeneity, both in terms of susceptibility and progression. This proposal makes use of hereditary cancer model in the Eker rat and a transgenic TSC2-mutant mouse model to identify post- initiation events that modulate kidney cancer phenotype. Both strains carry a germline mutation of the TSC2 gene that in humans, also predisposes the carriers to renal cell carcinoma as part of the tuberous sclerosis complex (TSC). The clinical features of the latter disease are highly variable even among family members sharing the same mutation. Those with mild forms of TSC live a normal life whereas those severely affected die prematurely of brain and kidney complications. Similarly, patients with low tumor burden fare better than those with heavy tumor load. In an attempt to understand the genetic determinants of phenotypic variation, observations in the Eker rat suggested a strain-dependent difference in renal tumor size at 18 months of age. Using the tools of quantitative biology, the investigators have demonstrated evidence for genetic factors governing tumor size that are unlinked to the TSC2 gene. The aims of this proposal are to determine the molecular identity of a dominant modifier of tumor burden and to detect and map other genetic elements that affect its phenotype (e.g., size, multiplicity, metastasis) in the two rodent models. Appreciation of these 'modifier' genes will impart new knowledge about the interplay between genes and environment during the development of complex diseases such as cancer.